Project Summary: A long-standing problem in the treatment of glioblastoma (GBM), the most common and deadly primary brain tumor, is delivery of therapeutics to highly invasive tumor cells that infiltrate the surrounding brain. Unlike the tumor core, invasive GBM cells cannot be surgically removed without catastrophic damage to healthy brain tissue. Furthermore, the location of central nervous system (CNS) tumors, including GBM, presents unique barriers to therapeutic delivery which limits effective doses of chemotherapy and radiation. Most systemically administered chemotherapeutics reach the brain in low concentrations in large part due to the blood-brain barrier (BBB). To overcome the BBB, local delivery approaches have been used to deliver therapeutics directly into the brain and affected region including Gliadel (bis-chloroethylnitorosourea [BCNU]) interstitial wafers and catheter- based convection-enhanced delivery (CED). Although both CED and interstitial wafers have proven safe and feasible in human clinical studies the dispersion of delivered therapeutics within brain tissue remains severely handicapped resulting in only modest improvements in treatment efficacy. Limited drug diffusion and dispersion in the brain are thought to be the limiting factors preventing more significant therapeutic efficacy against invasive brain cancer. Therefore, delivery strategies that overcome both the BBB and limitations to drug dispersion within the brain are needed and are highly likely to improve treatment efficacy. CED can be improved by using nanoparticle drug delivery carriers with dense polyethylene glycol (PEG) surface coatings that improve therapeutic delivery and distribution in vivo. These nanoparticles can also be targeted to glioma cells markers such as fibroblast growth factor-inducible 14 (Fn14), a promising new GBM delivery portal highly expressed on glioma cells but not in normal brain. Moreover, pilot studies suggest that Fn14 may also be expressed on tumor supporting stromal cells, and therefore may offer an opportunity to improve delivery of therapeutics to both the cancer and tumor supporting stromal cells. This proposal will evaluate the use of Fn14 targeted nanoparticles compared to the current standards of local delivery, to improve therapeutic pharmacokinetics and efficacy. The central hypothesis of this proposal is that PEG-coated, BCNU-loaded, targeted nanoparticles will (i) improve therapeutic distribution in brain tissue (ii) produce greater therapeutic efficacy and less toxicity compared to the current standard of local GBM chemotherapy by improving therapeutic delivery to glioma cells and the glioma- supporting cells of the microenvironment. In Aim 1, we will assess the pharmacokinetics and efficacy of BCNU delivered by nanoparticles via CED compared to local delivery standards In Aim 2, we will evaluate Fn14 expression in the stroma and determine the impact of Fn14 targeted and non-targeted delivery strategies on these cell populations in the microenvironment. We anticipate an Fn14 targeted nanoparticle therapeutic delivery approach will provide a safer method to improve efficacy while minimizing bystander effects, which could result in the application of this therapeutic strategy across a broad range of other brain diseases and invasive cancers.